Eye disease is a significant cause of morbidity in the U.S. and throughout the world. While therapies have improved over time for many eye diseases, there remain many others for which therapy is of limited or no benefit.
Diseases of the retina, including age-related macular degeneration (AMD), retinitis pigmentosa (RP), and diabetic retinopathy (DR), are major causes of legal blindness in the United States. AMD and RP share clinical and pathologic features including end-stage blindness due to photoreceptor and/or retinal pigment epithelium (RPE) cell death. DR is one of the most common complications of diabetes and the leading cause of blindness in people of working age in the United States and other industrialized countries. The estimated prevalence of diabetic retinopathy is nearly 30% and vision-threatening DR is nearly 5% in the adult population with diabetes (Zhang et al., 2010, JAMA 304; 649-656). The Eye Diseases Prevalence Research Group estimated in 2004 that approximately 4.1 million adults 40 years and older have diabetic retinopathy and that 1 of every 12 persons with diabetes in this age group has advanced, vision-threatening retinopathy. (The Eye Diseases Prevalence Research Group, 2004, Arch Ophthalmol 122:552-563).
Despite adequate glycemic and blood pressure control and lipid-lowering therapy, the number of DR patients continues to grow and therapeutic approaches remain limited. There is a great need for the development of new strategies to prevent and treat DR. Studies have shown that DR has prominent features of chronic, subclinical inflammation. Retinal vessel occlusion and degeneration is a typical feature of DR and is also a cause of neovascularization. Mechanisms leading to capillary degeneration may involve inflammatory cytokine-induced endothelial cell death since inflammatory cytokines such as TNF-α and IL-1β are also known to increase caspase 3 activity and potently induce endothelial cell apoptosis (Aveleira et al., 2010, Diabetes 59:2872-2882; Del Maschio et al., 1996, J Cell Biol 135:497-510). The apoptotic effect of inflammatory cytokines may even be exaggerated in the presence of hyperglycemia (Del Maschio, 1996).
Apoptosis of photoreceptors is a prominent feature in many retinal degenerations, including AMD and RP. Reactive oxygen species (ROS) have been implicated in the initiation and/or exacerbation of cell death in AMD (Fletcher, et al., Ophthalmic Res., Vol. 44, No. 3, pgs. 191-198 (2010); Beatty et al., Surv. Ophthalmol., Vol. 45, No. 2, pgs. 115-134 (2000); Winkler, Mol. Vis., Vol. 5, pg. 32 (1999); Johnson, Curr. Opin. Cln. Nutr. Metab. Care, Vol. 13, pgs. 28-33 (2010); Totan et al., Curr. Eye Res., Vol. 34, No. 12, pgs. 1089-1093 (2009)) and antioxidant vitamin therapy is currently one of the mainstays of treatment in non-exudative AMD and RP (Johnson, 2010; Hartong et al., Lancet, Vol. 368, pgs. 1795-1809 (2006)). Oxidative stress happens when ROS are overproduced or when endogenous antioxidant systems are impaired. Mitochondria have long been recognized as a key source of ROS formation during diabetes (Aiello et al., 1998, Diabetes Care 21:143-156). Mitochondria can generate ROS by leak of electrons to molecular oxygen at electron transport chain (ETC) complexes I, II and III (Jezek et al., 2005, Int J Biochem Cell Biol 37:2478-2503). In diabetes, the metabolism of glucose-derived pyruvate through the ETC complexes is increased because of high-glucose concentration within cells, resulting in superoxide overproduction by mitochondria (Giacco et al., 2010, Circ Res 107:1058-1070). Although not curative, reduction of risk of disease and stabilization of vision have been observed following antioxidant vitamin therapy (Flectcher, 2010; Beatty, 2000; Johnson, 2010; Hartong, 2006). Moreover, two of the top modifiable risk factors in AMD—smoking and light exposure—are thought to injure photoreceptors or RPE through ROS-mediated damage (Flectcher, 2010; Johnson, 2010).
Glaucoma is a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. A critical element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs). Strategies that delay or halt RGC loss have been recognized as potentially beneficial to preserve vision in glaucoma. In recent years, there has been an exponential increase in data regarding the molecular basis of RGC death resulting from experimental models of acute and chronic optic nerve injury as well as experimental glaucoma. A variety of molecular signals and/or mechanisms which might act alone or in concert can promote RGC death. Possible molecular mechanisms include: neurotrophic factor deprivation, toxic pro-neurotrophins, activation of intrinsic and extrinsic apoptotic signals, mitochondrial dysfunction, excitotoxic damage, and oxidative stress (Almasieh et al., 2012, Prog Retin Eye Res 31:152-81).
Dry, atrophic (nonexudative) age-related macular degeneration, defined as progressive age-related degeneration of the macula associated with retinal pigment epithelial changes including atrophy and drusen, is a common cause of vision loss in adults for which therapy is extremely limited. Patients often develop a slow progressive loss of vision over time. Vitamin therapies and other types of therapy are of limited benefit. More therapeutic options are available for patients with exudative age-related macular degeneration, which is associated with choroidal or subretinal neovascularization. Nevertheless, despite therapy such as laser or pharmacotherapy, many patients develop progressive vision loss. There is the need for therapies to reduce the risk of progressive vision loss in patients with both forms of age-related macular degeneration.
In summary, there is the need for more effective treatment of many common diseases of the eye, such as diseases of the retina, cornea, and glaucoma.